Preventives or remedies for endometriosis or uterine myoma

ABSTRACT

A drug effective for prevention and therapy of endometriosis and hysteromyoma is disclosed. The drug for prevention and/or therapy of endometriosis and/or hysteromyoma according to the present invention comprises as an effective ingredient a macrolide antibiotic.

TECHNICAL FIELD

[0001] The present invention relates to a drug for prevention and/ortherapy of endometriosis and/or hysteromyoma.

BACKGROUND ART

[0002] Endometriosis is a disease wherein endometrium orendometrium-like tissue ectopically proliferates at a site other thanthe inner surface of the cavity of uterus which is the natural sitethereof. The cause of endometriosis is unknown, and therapies such asseparation of the adhered tissues by surgery, administration of hormonesand administration of analgesics are performed. However, these therapiesare symptomatic treatments, and no complete therapy exists.

[0003] Hysteromyoma is benign tumor formed on the muscle of uterus, andmay cause emmeniopathy and metrorrhagia. If the myoma is large, itcompresses ambient organs, so that congestion in the pelvis, lumbago ordragging pain likely to occur. There is no therapy of hysteromyoma otherthan surgery, and the surgery is total extirpation of uterus inprinciple. Pharmacotherapy of hysteromyoma is not performed.

DISCLOSURE OF THE INVENTION

[0004] An object of the present invention is to provide a drug effectivefor prevention and/or therapy of endometriosis and/or hysteromyoma.

[0005] The present inventors intensively studied to discover thatmacrolide antibiotics are effective for prevention and/or therapy ofendometriosis and/or hysteromyoma, thereby completing the presentinvention.

[0006] That is, the present invention provides a drug for preventionand/or therapy of endometriosis and/or hysteromyoma, comprising amacrolide antibiotic as an effective ingredient. The present inventionalso provides a use of a macrolide antibiotic for the production of adrug for prevention and/or therapy of endometriosis and/or hysteromyoma.The present invention further provides a method for prevention and/ortherapy of endometriosis and/or hysteromyoma, comprising administering amacrolide antibiotic to a patient suffering from endometriosis and/orhysteromyoma, in an amount effective for the prevention and/or therapyof endometriosis and/or hysteromyoma.

[0007] By the present invention, a drug effective for prevention andtherapy of endometriosis, which can cure endometriosis was firstprovided. The number of patients suffering from endometriosis is nowrapidly increasing, and endometriosis is now one of the main causes ofmenorrhalgia and infertility. Thus, the present invention is thought togreatly contribute in the field of therapy of infertility, and therapyand prevention of menorrhalgia. Further, macrolide antibiotics areeffective for prevention and therapy of hysteromyoma of whichpathological symptoms are similar to those of endometriosis.

BEST MODE FOR CARRYING OUT THE INVENTION

[0008] As mentioned above, the drug for prevention or therapy ofendometriosis according to the present invention is effective for bothprevention and therapy of endometriosis, and comprises a macrolideantibiotic as an effective ingredient.

[0009] Macrolide antibiotics means a group of antibiotics having lactonerings (12- to 16-membered lactone ring (the number of atoms constitutingthe ring is 12 to 16), and having (a) neutral or (an) amino sugar(s).Examples of the macrolide antibiotics which may be employed in thepresent invention include clarithromycin, roxithromycin, azithromycin,erythromycin, josamycin, leucomycins, spiramycins, carbomycins, tylosin,angolamycin, kitasamycin, acetylspiramycin, midecamycin, oleandomycin,mirosamycin and maridomycin, as well as hydrates, non-toxic salts andderivatives thereof, although not restricted thereto. The term“derivative” herein means those compounds having the same basal skeletonas the original compound, but the substituents attached to the lactonering and/or sugar(s) are changed, and such derivatives may be used aslong as they have antibiotic properties. Examples of the non-toxic saltinclude hydrochloric acid salt, sulfuric acid salt, tartaric acid saltand citric acid salt, although the non-toxic salts are not restrictedthereto. As the macrolide antibiotic, those having 14-membered or15-membered lactone ring are preferred, and those in which two sugarunits are bound are preferred. Especially, clarithromycin, roxithromycinand azithromycin are preferred.

[0010] The drug for prevention and/or therapy of endometriosis accordingto the present invention may be administered by oral administration orparenteral administration such as intravenous, subcutaneous,intramuscular or rectal administration, and oral administration ispreferred because it is simple. Although the administration dose isappropriately selected depending on the degree of the symptom of thepatient, type of the macrolide antibiotic and the like, the dose isusually about 300 to 500 mg in terms of the amount of the macrolideantibiotic per day per adult. The drug is effective at the dose employedfor the therapies of infectious diseases.

[0011] Adenomyosis of uterus is the state that the endometrium orendometrium-like tissue ectopically proliferates in myometrium, so thatit is a form of endometriosis and is included in endometriosis(“Surgical Pathology”, p.713-715, published by Bunkodo; “ClinicalHistopathology”, p.661, published by Kyorin Shoin).

[0012] The present inventor intensively studied the findings ofhysteromyoma. As a result, existence of mast cells and degranulationwere observed. Thus, it was confirmed that the findings thereof are thesame as the endometriosis from the observation of human cases.Therefore, macrolide antibiotics are effective for the therapy andprevention of hysteromyoma, similarly to endometriosis.

[0013] As for the macrolide antibiotics used for the therapy and/orprevention of hysteromyoma, as well as the administration route andadministration dose, the above-described explanations for theendometriosis can be applied as they are.

[0014] As for the formulation of the drug, any formulation methodsordinarily employed in the field of pharmaceuticals may be employed. Forexample, the macrolide antibiotic may be granulated together with anadditive such as a polyoxyethylenesorbitan fatty acid ester, propyleneglycol or sodium laurate, and the resultant may be made into tablets,but the formulation method is not restricted thereto. For example, adrug may be formulated by mixing 50 mg of clarithromycin and 34 mg ofpolyoxyethylenesorbitan fatty acid ester, granulating the resultingmixture and making tablets from the granulated mixture. Needless to say,the formulation method is not restricted thereto.

[0015] Since macrolide antibiotics have been used as therapeutic agentsfor various infectious diseases, safeties thereof to the extent demandedfor pharmaceuticals have been confirmed.

[0016] The present invention will now be described more concretely byway of examples. However, the present invention is not limited to thefollowing examples.

EXAMPLE 1 Therapeutic Effect for Endometriosis by Clarithromycin

[0017] Endometriosis model rats were prepared by the method described inMichael W. Vernon et al., FERTILITY AND STERILITY, Vol. 44, No. 5,November 1985. That is, endometriosis model rats were prepared asfollows: Sprague-Dawley rats (female) of 8 weeks old were acclimatizedfor 2 weeks under 12 hours light-dark condition. From each rat, rightuterine horn was excised under general anesthesia with sevoflurane andketamine hydrochloride, and a tissue piece sizing 5 mm×5 mm was preparedtherefrom. The tissue piece was subjected to autotransplantation suchthat the endometrium surface is attached to peritoneum.

[0018] From 24 hours after the preparation of the endometriosis modelrats, commercially available clarithromycin tablets (trademark “ClarithTablet 50 for Children” prepared by Taisho Pharmaceutical Co., Ltd) wereorally administered to the rats for 3 days. The dose of administrationwas 10 mg/kg per day in terms of clarithromycin. Clarithromycin was notadministered to control animals. Seven days after the preparation of themodel rats, at which the model lesion reached its peak, the peritoneumtissue including the graft up to the abdominal muscle was excised toobtain a lesion sample. From the thus obtained samples, light microscopespecimens (hematoxylin-eosin staining, toluidine blue staining) andelectron microscope specimens (uranium-lead double staining) wereprepared, and the existence of invaded mast cells, which is a symptom ofendometriosis, and the degree of interstitial proliferative lesion wereobserved.

[0019] As a result, in the control group, invasion of mast cells andinterstitial proliferative lesion were observed. In contrast, in theclarithromycin-administered group, invasion of mast cells was notobserved, and the degree of interstitial proliferative lesion wasapparently reduced.

EXAMPLE 2 Therapeutic Effect for Endometriosis by Roxithromycin

[0020] The same procedures as in Example 1 were repeated except thatroxithromycin (trademark “Rulid Tablet 150”, commercially available fromEisai Co., Ltd.) was used in place of clarithromycin. The administrationdose was 6 mg/kg per day in terms of roxithromycin. As a result, in thecontrol group, invasion of mast cells and interstitial proliferativelesion were observed. In contrast, in the roxithromycin-administeredgroup, invasion of mast cells was not observed, and the degree ofinterstitial proliferative lesion was apparently reduced.

EXAMPLE 3 Therapeutic Effect for Endometriosis by Azithromycin

[0021] The same procedures as in Example 1 were repeated except thatazithromycin (trademark “Zithromax Tablet 250 mg”, commerciallyavailable from Pfizer Pharmaceuticals Inc.) was used in place ofclarithromycin. The administration dose was 10 mg/kg per day in terms ofroxithromycin. As a result, in the control group, invasion of mast cellsand interstitial proliferative lesion were observed. In contrast, in theazithromycin-administered group, invasion of mast cells was notobserved, and the degree of interstitial proliferative lesion wasapparently reduced.

1. A drug for prevention and/or therapy of endometriosis and/orhysteromyoma, comprising a macrolide antibiotic as an effectiveingredient.
 2. The drug for prevention and/or therapy according to claim1, wherein said macrolide antibiotic is clarithromycin, roxithromycin orazithromycin.
 3. The drug for prevention and/or therapy according toclaim 1 or 2, which is a drug for prevention and/or therapy ofendometriosis.
 4. Use of a macrolide antibiotic for the production of adrug for prevention and/or therapy of endometriosis and/or hysteromyoma.5. The use according to claim 4, wherein said macrolide antibiotic isclarithromycin, roxithromycin or azithromycin.
 6. The use according toclaim 4 or 5, which is used for prevention and/or therapy ofendometriosis.
 7. A method for prevention and/or therapy ofendometriosis and/or hysteromyoma, comprising administering a macrolideantibiotic to a patient suffering from endometriosis and/orhysteromyoma, in an amount effective for the prevention and/or therapyof endometriosis and/or hysteromyoma.
 8. The method according to claim7, wherein said macrolide antibiotic is clarithromycin, roxithromycin orazithromycin.
 9. The method according to claim 7 or 8, wherein saidmacrolide antibiotic in an amount effective for the prevention and/ortherapy of endometriosis is administered to a patient suffering fromendometriosis.